Tuberculosis (TB), caused by the intracellular bacteria Mycobacterium tuberculosis (Mtb), is the second-leading cause of death worldwide from infection. Following inhalation, Mtb are phagocytosed by macrophages at the epithelial barrier of the lung, eliciting an inflammatory response and recruitment of other immune cells from the blood. While in the circulation, infected phagocytes can disseminate throughout the body, leading to infection at extrapulmonary (EP) sites. In South Africa, which has the highest incidence of TB in the world of 981/100,000 population, 15.5 percent of all new TB cases in 2010 were EPTB. One of the most debilitating forms of EPTB is spinal TB (Pott's Disease). The tissue composition and microenvironment of the skeletal system varies greatly from that of the lung. In the spine, Mtb infection is contained in the form of a cold epidural abscess, associated with bone and cartilage destruction, which may cause collapse of the spinal column, deformity and neurological complications. There is limited understanding of EPTB disease pathogenesis, which hinders control of the epidemic. I will determine the specific mechanisms by which Mtb infection of the spine drives excessive inflammation and inappropriate bone and cartilage homeostasis. Specific Aim 1 will define the pathways and molecular networks that underlie Mtb-induced bone and cartilage destruction by utilizing microarray, histological and mass spectrometry analysis. Specific Aim 2 will test the hypothesis that a combinatorial signature of markers of bone/cartilage turnover and Mtb-driven immunity will be detectable in the circulation of patients with Pott's disease. TB is a major opportunistic infection in HIV and HIV is known to affect bone health. In Specific Aim 3, I will therefore investigate the impact of HIV co-infection n 1) the mechanisms causing tissue-specific pathology in Spinal TB and 2) the expression of candidate biomarkers, in the circulation. All studies will be conducted on excised, granulomatous tissue and bloods from adult patients from Durban, South Africa whose course of treatment for spinal TB necessitates surgery. This study will address an outstanding question in TB research, namely a molecular definition of the immunopathogenesis of Spinal TB. Ultimately, the results of this project can contribute towards improved diagnostic tools, monitoring strategies and therapeutic approaches in TB patients.